Coatings comprising self-assembled molecular structures and a method of delivering a drug using the same

ABSTRACT

A coating for an implantable medical device is disclosed, the coating including a self-assembled molecular structure. The coating can be used for altering the release rate of a therapeutic substance from the implantable device.

BACKGROUND

1. Field of the Invention

This invention is directed to coatings for implantable medical devices,such as pacing leads.

2. Description of the State of the Related Art

Pacing leads are widely used for treatment of a variety of heartailments, for example, irregularity of the heart beat. It is desirableto be able to use the pacing lead not only for defibrillation, but alsoas a vehicle for providing biological therapy.

Biological therapy can be achieved by medicating pacing leads. Onemethod for medicating pacing leads involves the use of a polymericcarrier coated onto the surface of a pacing lead. A solution whichincludes a solvent, a polymer dissolved in the solvent, and atherapeutic substance dispersed in the blend is applied to the pacinglead. The solvent is allowed to evaporate, leaving on the pacing leadsurface a coating of the polymer and the therapeutic substanceimpregnated in the polymer.

For the purposes of pharmacological therapy, it is important to maintainthe concentration of the drug at a therapeutically effective level foran acceptable period of time. Hence, controlling a rate of release ofthe drug from the pacing lead is important, especially in such a way soas to decrease the release rate of the drug from the underlying matrix.It is also desirable to be able to rapidly increase the rate of releaseof the drug during the process of defibrillation, and then to returnquickly to slow delivery of the drug.

In view of the foregoing, coatings capable of pulsatile drug deliveryfrom pacing leads, are desired. Embodiments of the present inventiondisclose such coatings and methods for fabricating thereof.

SUMMARY

According to one embodiment of the present invention, a coating for animplantable medical device is provided, the coating comprises a polymerlayer having a crystalline structure, wherein the structure of thepolymer becomes less crystalline when the polymer is exposed to astimulus, and wherein, when the stimulus is terminated, the structure ofthe polymer returns back to essentially the same degree of crystallinityor a more crystalline structure than that of when the polymer wasexposed to the stimulus. The polymer layer can be prepared from acompound which includes a methylene-based chain or a silicone-basedchain and at least one reactive functional group, for example, octadecylisocyanate or 1-octadecanol.

According to another embodiment of the present invention, a method forlocal delivery of a drug is provided, the method comprises implanting amedical device carrying a drug-containing coating in a patient for thesustained local delivery of the drug and applying an electric currentfor an interval of time to the device for increasing a rate of deliveryof the drug. The coating comprises a polymeric reservoir layer disposedon at least a portion of the device, and a layer of a self-assembledstructure of molecules of an organic or elemento-organic substancebonded to the reservoir layer. The reservoir layer is made from apolymer which includes at least one reactive functional group, forexample, from poly(ethylene-co-vinyl alcohol), poly(methylmethacrylate-co-2-hydroxyethyl methacrylate), poly(2-hydroxyethylmethacrylate), or poly(amino acid).

DETAILED DESCRIPTION

A coating for an implantable medical device, such as a pacing lead, canbe applied onto the device using conventional coating techniques, forexample, spraying or dipping. According to one embodiment of the presentinvention, the coating can include a drug-polymer layer (also referredto as “a reservoir layer”), a topcoat layer, and an optional primerlayer. The drug-polymer layer can be applied directly onto the surfaceof the pacing lead to serve as a reservoir for an active agent (or adrug) which is incorporated into the reservoir layer. The optionalprimer layer can be applied between the device and the reservoir layerto improve the adhesion of the reservoir layer to the device. Thetopcoat membrane layer can be applied over the reservoir layer. Thetopcoat layer, which can be essentially free from any therapeuticsubstances or drugs, serves as a rate limiting membrane which furthercontrols the rate of release of the drug. By forcing the agent todiffuse through an additional coating layer, the release of the activeagent may be slowed.

The topcoat layer is made of a self-assembled molecular structure(SAMS). For the purposes of this invention, SAMS is defined as a thincrystalline film of an ordered structure of molecules of an organic orelemento-organic substance. The thin film forms on a surface of asubstrate when the surface is exposed to the molecules of the substanceat suitable reaction conditions. One of the conditions can be additionof catalysts. “Ordered structure” is defined as a closely packedstructure, being for example about 4 Å apart, and can display a tiltangle of between about 30° and 35° from the normal of the substrate.“Thin” is defined as a layer having a thickness on a micron scale, fromabout 0.1 to about 5 μm.

At ambient temperature, SAMS serves as a barrier effectively preventingthe drug from significantly diffusing out of the coating prior todeployment of the coated pacing lead (e.g., during storage andtransportation of the coated pacing lead). After the pacing lead hasbeen placed into a human body, the pacing lead coated with the coatingwhich includes a SAMS can be operated as a drug delivery vehicle capableof a dual mode pulsatile delivery.

In the first mode of delivery, the release regime can be either zerorelease or steady background release, depending on the chemicalcomponents forming the SAMS. In this mode, after the coated pacing leadhas been placed into the patient's body, the pacing lead becomes exposedto the body temperature (approximately 37° C.). At such temperature, theSAMS undergoes at least a partial transformation. The transformationleads to creating a molecular structure which is still predominantlycrystalline but includes some amorphous portions, allowing the drug tostart steadily eluting at a slow and substantially constant rate fromthe pacing lead.

In the second mode of delivery, the drug is delivered in a “burst”regime. The burst mode can be used when it is desirable to provide for ashort period of a more substantial rate of release. For the purposes ofthe present invention the term “burst” mode of delivery is defined as aregime where a release rate is at least twice as high as the backgroundrelease rate.

The pacing lead can be used for treatments of arrhythmia. When the heartrhythm of a patient becomes irregular and has to be corrected, anelectric signal is generated at an electrode of the pacing lead tocorrect the rhythm. This treatment technique is known to those havingordinary skill in the art. It can be beneficial for the patient toreceive an increased dose of medication while the heart rhythm is beingcorrected. The burst delivery mode allows for delivery of such increaseddose for a short period of time.

During the process of correction of the heart rhythm, the electricsignal can also lead to inducing further crystalline/amorphoustransition of the SAMS. As a result, the barrier properties of thetopcoat layer made of a SAMS can be significantly reduced allowing therapid release of the drug. When the electric signal is terminated, theSAMS self-heals quickly, restoring the initial predominantly crystallinestructure. Therefore, after the electric signal is terminated, thebarrier properties of the SAMS-based topcoat membrane are essentiallyrestored, returning the device to the first mode of delivery.

The electric signal, that is sent to the electrode of the pacing lead,typically has parameters used in defibrillating devices, for example, acurrent of about 15 Amperes, voltage of about 700 Volts, and a pulseduration of about 10 milliseconds. The cyclic process of applying theelectric current can be repeated as often as necessary.

Examples of suitable substance that can be used to prepare SAMS includesubstances having a general formula (I)R-A-R′  (I),where A represents a methylene chain or a silicone chain, and R and R′are functional groups, at least one of which is a reactive functionalgroup.

SAMS can be prepared by applying substance (I) on a device havingreservoir layer deposited over at least a portion of the device. For thepurposes of the present invention, substance (I) is referred to as a“SAMS-forming substance.” Any suitable SAMS-fabrication technique knownto those having ordinary skill in the art can be used. For example, aSAMS-forming substance can be applied from a solution. Typically, aSAMS-forming substance can be dissolved in an appropriate solvent, suchas tetrahydrofuran (THF) or hexanes. The concentration of theSAMS-forming substance in the solution can be typically between 1 and10% by volume. The device can then be immersed into the solution,usually for a short period of time which can be between about 30 minutesand a few hours, followed by rinsing with a solvent, e.g. THF, to removethe unreacted residues, and vacuum drying.

According to one embodiment of the present invention, methylenechain-based SAMS can be used to form the topcoat layer. For themethylene chain-based SAMS, “A” in formula (I) is the methylene group—CH₂—. Thus, the methylene chain-based SAMS comprises a methylene chainhaving functional groups on both ends of the chain. The structure of asubstance forming a SAMS can be represented by a general formula (II)R—(CH₂)_(n)—R′,  (II)

where the substitutents are the same (R═R′) or different (R≠R′).Methylene chains can typically include between 10 and 25 carbon atoms(n=10−25). R and/or R′ can usually include hydrogen, methyl, hydroxyl,carboxyl, sulfonyl, acetate, trifluoro acetate, benzoate, isocyanate,epoxy, amino, thiol, or acrylic groups. At least one of R and R′ is areactive group. For example, if R is methyl (a non-reactive group), R′will be a reactive group, e.g., hydroxyl, isocyanate or epoxy group.

SAMS can be chemically bonded to the reservoir layer. To bond the SAMS,covalent bonds are formed between the SAMS and the reservoir layer usingthe functionalities present in the SAMS-forming substance and in thepolymer forming the reservoir layer.

One example of a polymer having functional groups that can be used forbonding SAMS is poly(ethylene-co-vinyl alcohol) having a general formula—[CH₂—CH₂]_(p)—[CH₂—CH(OH)]_(q)—, where “p” and “q” are integers.Poly(ethylene-co-vinyl alcohol) is known under the trade name EVAL andis manufactured by EVAL Company of America of Lisle, Ill. EVAL is alsodistributed commercially by Aldrich Chemical Company of Milwaukee, Wis.

EVAL is a product of hydrolysis of ethylene-vinyl acetate copolymers.Those having ordinary skill in the art of polymer chemistry willunderstand that EVAL may also be a terpolymer and may include up to 5%(molar) of units derived from styrene, propylene and other suitableunsaturated monomers.

The hydroxyl functionality of EVAL can be used for chemical bondingSAMS. Instead of EVAL, other polymers having hydroxyl groups can beutilized for preparing the reservoir layer and for bonding SAMS. Otherexamples of such polymers include poly(butylmethacrylate-co-2-hydroxyethyl methacrylate) [P(BMA-HEMA)] having theformula

and poly(2-hydroxyethyl methacrylate) (PHEMA) having the formula

where “x,” “y,” and “z” are integers.

According to one embodiment, an isocyanate-terminated SAMS-formingsubstance can be bonded to a reservoir polymer containing hydroxylgroups. In the isocyanate-terminated SAMS-forming substance, at leastone of R and R′ in formula (I) is the isocyanate group —N═C═O. Examplesof suitable isocyanate-terminated SAMS-forming substances that can bebonded to the polymer of the reservoir layer include octadecylisocyanate and dodecyl isocyanate.

Due to the presence of the isocyanate groups, the isocyanate-terminatedSAMS-forming substance is chemically very active and readily reacts withEVAL. The isocyanate group, having strong electron accepting properties,reacts with nucleophilic hydroxyl group of EVAL, as illustrated in caseof octadecyl isocyanate by reaction scheme (III):

The conditions under which reaction (III) is conducted can be determinedby those having ordinary skill in the art. For example, the reaction canbe carried by preparing a solution of octadecyl isocyanate and addingthe solution to EVAL. The temperature can be maintained at between about40° C. and about 60° C., and the reaction can be conducted for not morethan about 1 hour.

Since the isocyanate group easily becomes inactive as a result ofhydrolysis, reaction (III) is conducted in an inert water- andmoisture-free environment, for example, under dry nitrogen or argonatmosphere using anhydrous hexane or tetrahydrofuran as the solvent foroctadecyl isocyanate. The reaction can be catalyzed by adding to thesolution of octadecyl isocyanate between about 0.1 mass % and about 0.5mass %, for example, about 0.3 mass % of the catalyst dibutyltindilaurate having the formula [CH₃—(CH₂)₁₀—C(O)O]₂Sn[(CH₂)₃—CH₃]₂ or byadding another suitable catalyst.

If desired, EVAL can be replaced with another acceptable polymercontaining hydroxyl groups. For example, isocyanate-terminatedSAMS-forming substance can be bonded to PHEMA utilizing hydroxyl groupsof the PHEMA. As a result, the SAMS is firmly bonded to EVAL or anotheracceptable hydroxyl-containing polymer to form the urethane product ofreaction (III).

According to another embodiment of the present invention, instead of apolymer containing hydroxyl groups, a polymer containing alternativefunctional groups can be used for making the reservoir layer. Thealternative functional groups can be used to bond a SAMS-formingsubstance to the reservoir layer. Examples of suitable alternativegroups include amino groups, carboxyl groups and thiol groups.

One example of a polymer containing amino groups that can be used formaking the reservoir layer is poly(amino acid). To bond a SAMS-formingsubstance to this reservoir layer, the alkylation of amines techniquecan be used. In this case, the SAMS-forming substance provides thehydroxyl functionality and the reservoir polymer provides the aminofunctionality. The SAMS-forming substance can be a hydroxyl-terminatedcompound, such as a long-chained aliphatic alcohol or diol which can berepresented as formula (II), where either R or R′, or both, is ahydroxyl group. Examples of such compounds include 1-octadecanol (alsoknown as stearyl alcohol), and dodecanol.

To bond 1-octadecanol to the aminated reservoir, as a first step1-octadecanol can be preliminarily derivatized by tosylation (treatmentwith tosyl chloride), or alternatively by tresylation (by reacting withtresyl chloride). Tosyl chloride (TsCl) is a sulfonyl derivative oftoluene, p-toluenesulfonyl chloride, having the formula CH₃—C₆H₄—SO₂Cl.Tresyl chloride or 2,2,2-trifluoroethanesulphonyl chloride (TrCl) is analiphatic derivative of sulfonic acid having the formula CF₃—CH₂—SO₂Cl.The conditions under which the tosylation or tresylation is carried areknown to those having ordinary skill in the art.

As a result of tosylation, tosyl group is attached to 1-octadecanol viahydroxy group to yield the toluenesulfoester as illustrated by reaction(IV):CH₃—(CH₂)₁₇—OH+CH₃—C₆H₄—SO₂Cl→CH₃—CH₂)₁₇—O—SO₂—C₆H₄—CH₃  (IV)

Alternatively, if tresylation is used to derivatrize 1-octadecanol, theprocess can be illustrated as shown by reaction (V) and as a result thetresyl group is attached to 1-octadecanol via hydroxyl group:CH₃—(CH₂)₁₇—OH+CF₃—CH₂—SO₂Cl→CH₃—(CH₂)₁₇—O—SO₂—CH₂—CF₃  (V)

As a second step of conjugating, the aminated polymer of the reservoiris reacted with the derivatized 1-octadecanol. Since toluenesulfonicacid is known to be a very strong acid, its anion, CH₃—C₆H₄—SO₃—, is anexcellent leaving group in the nucleophilic substitution alkylationreaction of a primary amine. Accordingly, the tosylated 1-octadecanol(the product of reaction (IV) obtained as described above), readilyreacts with the aminated polymer of the reservoir as schematically shownby the alkylation reaction (VI):X—NH₂+CH₃—(CH₂)₁₇—O—SO₂—C₆H₄—CH₃→X—NH—(CH₂)₁₇—CH₃  (VI),where X symbolizes the backbone of the polymer forming the reservoir.

The conditions under which reaction (VI) is conducted can be determinedby those having ordinary skill in the art. The reaction of tresylated1-octadecanol and the aminated polymer forming the reservoir layer issimilar to reaction (VI). As a result, 1-octadecanol is bonded to thepolymer of the reservoir layer to form the secondary amine product ofreaction (VI).

Instead of the hydroxyl-terminated SAMS-forming substance, acarboxyl-terminated SAMS-forming substance can be used, for example acarbonic acid. In such a case, the carboxyl-terminated SAMS-formingsubstance can be conjugated to the amino group-containing polymer of thereservoir layer to form an amide, under conditions that can bedetermined by those having ordinary skill in the art.

The polymer of the reservoir layer can be any polymer otherwise suitablefor making coatings for implantable medical devices such as pacingleads. The above-described embodiments discuss reservoir layers made ofpolymers that include a reactive group, such as hydroxyl, amino, oracrylate group. However, the polymers not having reactive groups can bealso used to make the reservoir layer. Polymers without reactive groupscan be pre-treated to generate the reactive groups so as to enable thebonding of the SAMS-forming substance to the polymer of the reservoirlayer.

For example, hydroxyl groups can be generated on the surface of areservoir layer not originally containing hydroxyl groups by partiallyoxidizing the polymer forming the reservoir layer. The partial oxidationcan be accomplished using low energy surface treatments known to thosehaving ordinary skill in the art. Examples of such treatments includeoxidative gas plasma treatment, corona discharge and electron beamtreatment, oxidative gas treatments using, for example, ozone or amixture of fluorine and oxygen, and chemical etching treatments using,for example, nitric acid or chromic acid.

In another embodiment, amino groups can be generated on the surface of areservoir layer not originally containing amino groups. For example, thesurface of the reservoir polymer can be treated by oxygen plasma togenerate aldehyde or ketone groups, followed by reaction withhydroxylamine NH₂—OH and reduction yielding amino groups on the surfaceof the reservoir polymer. Alternatively, the surface of the reservoirpolymer can be treated with ammonium and hydrogen gas plasma to generateamino groups.

In addition to EVAL, PHEMA, P (BMA-HEMA), and poly(amino acid) discussedabove, representative examples of polymers that can be used to fabricatethe reservoir layer include poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyalkyleneoxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen,cellulose, starch, collagen and hyaluronic acid), polyurethanes (such asCORETHANE available from Pfizer Corp. of New York or ELASTEON availablefrom AorTech Biomaterials Co. of Chatswood, Australia), silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers (such as poly(butylmethacrylate), poly(ethyl methacrylate) or poly(hydroxyethylmethacrylate)), vinyl halide polymers and copolymers (such as polyvinylchloride), polyvinyl ethers other than polyacetals, polyvinylidenehalides (such as polyvinylidene fluoride and polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose. If the selected polymer does not have reactivegroups, it can be treated as discussed above to introduce the desiredreactive groups.

The drug-containing reservoir layer can be formed on the pacing lead inany suitable manner. For example, a coating composition including asolvent, a polymer, and the drug can be applied to the pacing lead byimmersing the pacing lead in the coating composition or by spraying thecoating composition onto the pacing lead. Following evaporation of thesolvent, a reservoir layer of the polymer and the drug incorporated inthe polymer is formed on the pacing lead.

Alternatively, a polymeric reservoir layer, free from drugs, can beformed on the pacing lead by any suitable method. The drug can then beintroduced into the reservoir layer by, for example, placing the coatedpacing lead into a reaction flask containing the drug, allowing theagent to diffuse across the concentration gradient into the reservoirlayer, and drying the pacing lead to form an drug-containing reservoirlayer on the pacing lead.

The drug that can be used in the pacing lead coating can includeanti-inflammatory corticoids, for example, dexamethasone acetate ordexamethasone sodium phosphate. Although the present invention has beendescribed with reference to a pacing lead, SAMS can also be used inconjunction with other implantable devices such as stents.

EXAMPLES

Some embodiments of the present invention are further illustrated by thefollowing example.

Example 1

A composition can be prepared by mixing the following components:

(a) about 2.0 mass % of EVAL;

(b) about 0.7 mass % of dexamethasone acetate; and

(c) the balance, DMAC solvent.

The composition can be applied onto the surface of a pacing lead, forexample, FLEXEXTEND available from Guidant Corp., by spraying and driedto form a drug-polymer (reservoir) layer. A spray coater can be used,having a 0.014 inch fan nozzle maintained at about 60° C. with a feedpressure of about 0.2 atm (about 3 psi) and an atomization pressure ofabout 1.35 atm (about 20 psi). An total of about 500 μg of the wetcoating can be applied. The drug-polymer layer can be baked at about 50°C. for about two hours.

The pacing lead coated with the drug-polymer layer as described above,can be placed in a round bottom flask. About 1 ml of a SAMS-formingmaterial, for example, octadecyl isocyanate, and about 20 ml of apoor-swelling anhydrous solvent, such as THF, can be added to the flask.The contents of the flask are kept in an inert atmosphere, for example,nitrogen or argon atmosphere.

The solution contained in the flask is heated, for example, to about 60°C., and a catalyst, for example dibutyltin dilaurate can be added to thesolution. The amount of catalyst can be about 0.3 mass % of the weightof octadecyl isocyanate. The reaction can be maintained for about 30minutes at about 60° C. to yield a SAMS formed on the pacing lead,followed by rinsing with fresh THF and vacuum drying.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method for local delivery of a drug, comprising acts of: (a)implanting a medical device carrying a drug-containing coating in apatient for the sustained local delivery of the drug, wherein thecoating comprises a polymeric reservoir layer disposed on at least aportion of the device, and a layer of a self-assembled structure ofmolecules of an organic or elemento-organic substance bonded to thereservoir layer; and (b) applying an electric current for an interval oftime to the device to cause the self-assembled structure of molecules totransform from a crystalline structure to an amorphous structure so asto increase for increasing the rate of release of the drug, whereinafter the electric current is terminated, the crystallinity of theself-assembled structure of molecules returns back to essentially thesame degree of crystallinity or a more crystalline structure than thatof when the self-assembled structure of molecules was exposed to thecurrent, wherein the self-assembled molecular structure is prepared froma compound comprising a methylene chain having between 10 and 25 carbonatoms.
 2. The method of claim 1, wherein the self-assembled structure isprepared from a compound which includes at least one reactive functionalgroup.
 3. The method of claim 2, wherein the reactive functional groupis selected from a group consisting of hydroxyl, carboxyl, sulfonyl,isocyanate, epoxy, amino, thiol, and acrylic.
 4. The method of claim 1,wherein the self-assembled molecular structure is prepared from acompound selected from a group consisting of octadecyl isocyanate,dodecyl isocyanate, dodecanol, and 1-octadecanol.
 5. The method of claim1, wherein the polymer of the reservoir layer includes at least onereactive functional group.
 6. The method of claim 5, wherein thereactive functional group is selected from a group consisting ofhydroxyl, carboxyl, amino, and thiol.
 7. The method of claim 1, whereinthe polymer of the reservoir layer is selected from a group consistingof poly(ethylene-co-vinyl alcohol), poly(butylmethacrylate-co-2-hydroxyethyl methacrylate), poly(2-hydroxyethylmethacrylate), and poly(amino acid).
 8. The method of claim 1, whereinthe self-assembled structure comprises the following formula:R—(CH₂)_(n)—R′, wherein each of R and R′ is independently a hydrogen,methyl, hydroxyl, carboxyl, sulfonyl, acetate, trifluoro acetate,benzoate, isocyanate, epoxy, amino, thiol, or acrylic group.
 9. Themethod of claim 1, wherein the self-assembled structure comprises thefollowing formula: R—(CH₂)_(n)—R′, wherein at least one of R or R′ is areactive group.
 10. The method of claim 1, wherein the self-assembledstructure comprises the following formula: R—(CH₂)_(n)—R′, wherein atleast one of R or R′ is an iscocyanate, epoxy or hydroxyl group.
 11. Themethod of claim 1, wherein the self-assembled structure comprises ahydroxyl-terminated compound.
 12. The method of claim 1, wherein theself-assembled structure comprises a isocyanate-terminated compound. 13.The method of claim 1, wherein the self-assembled structure comprises acarboxyl-terminated compound.